Sustained somatostatin gene expression reverses kindling-induced increases in the number of dividing Type-1 neural stem cells in the hippocampi of behaviorally responsive rats.

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Sustained somatostatin gene expression reverses kindling-induced increases in the number of dividing Type-1 neural stem cells in the hippocampi of behaviorally responsive rats.

Epilepsy Res. 2019 Jan 11;150:78-94

Authors: Leibowitz JA, Natarajan G, Zhou J, Carney PR, Ormerod BK

Abstract
Neurogenesis persists throughout life in the hippocampi of all mammals, including humans. In the healthy hippocampus, relatively quiescent Type-1 neural stem cells (NSCs) can give rise to more proliferative Type-2a neural progenitor cells (NPCs), which generate neuronal-committed Type-2b NPCs that mature into Type-3 neuroblasts. Many Type-3 neuroblasts survive and mature into functionally integrated granule neurons over several weeks. In kindling models of epilepsy, neurogenesis is drastically upregulated and many new neurons form aberrant connections that could support epileptogenesis and/or seizures. We have shown that sustained vector-mediated hippocampal somatostatin (SST) expression can both block epileptogenesis and reverse seizure susceptibility in fully kindled rats. Here we test whether adeno-associated virus (AAV) vector-mediated sustained SST expression modulates hippocampal neurogenesis and microglial activation in fully kindled rats. We found significantly more dividing Type-1 NSCs and a corresponding increased number of surviving new neurons in the hippocampi of kindled versus sham-kindled rats. Increased numbers of activated microglia were found in the granule cell layer and hilus of kindled rats at both time points. After intrahippocampal injection with either eGFP or SST-eGFP vector, we found similar numbers of dividing Type-1 NSCs and -2 NPCs and surviving BrdU+ neurons and glia in the hippocampi of kindled rats. Upon observed variability in responses to SST-eGFP (2/4 rats exhibited Grade 0 seizures in the test session), we conducted an additional experiment. We found significantly fewer dividing Type-1 NSCs in the hippocampi of SST-eGFP vector-treated responder rats (5/13 rats) relative to SST-eGFP vector-treated non-responders and eGFP vector-treated controls that exhibited high-grade seizures on the test session. The number of activated microglia was upregulated in the GCL and hilus of kindled rats, regardless of vector treatment. These data support the hypothesis that sustained SST expression exerts antiepileptic effects potentially through normalization of neurogenesis and suggests that abnormally high proliferating Type-1 NSC numbers may be a cellular mechanism of epilepsy.

PMID: 30735971 [PubMed - as supplied by publisher]

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